Intermediate for preparing anamorelin as well as preparation method and application of intermediate

Abstract

The invention relates to an intermediate for preparing anamorelin as well as a preparation method and application of the intermediate. Specifically, the invention discloses a compound as shown in a formula I-2, and the definitions of all groups and substituent groups are described in the specification. The compound provided by the invention is modified by a chiral adjuvant, and a chiral group can be introduced, so that high-chiral-purity anamorelin is prepared. The invention also provides a preparation method of the compound as shown in the formula I-2 and application of the compound in preparation of anamorelin and intermediates thereof or other drugs.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to an intermediate for preparing anamorelin, a preparation method thereof, and an application thereof. Background Art

[0002] On December 11, 2020, anamorelin received the world's first approval for the treatment of cancer cachexia. An application for manufacturing and marketing authorization for anamorelin was submitted in Japan for the treatment of cancer cachexia in four cancer types: non-small cell lung cancer, pancreatic cancer, and colorectal cancer. Currently, it is the only drug in the world that effectively improves cancer cachexia.

[0003] The compound represented by formula II is a key intermediate for the synthesis of anamorelin.

[0004]

[0005] The synthesis of anamorelin is currently mainly carried out by a splitting method. Patent CN 115960080 utilizes the carboxyl group in the structure and uses R-configured phenylethylamine for splitting. The operation is relatively cumbersome. According to the patented process, three recrystallizations are required after splitting to achieve the required optical purity, and the overall yield is relatively low.

[0006]

[0007] The paper J.Med.Chem.1998,41,2439-2441 and patent CN110402245 are based on the alkalinity of piperidine in the intermediate structure and use chiral acid for separation. However, they also require multiple recrystallization operations and have low overall yields.

[0008]

[0009] Therefore, there is an urgent need in the art to develop a key intermediate compound with a novel structure for preparing anamorelin, wherein the intermediate can be efficiently used to prepare anamorelin with good chiral purity. Summary of the Invention

[0010] The object of the present invention is to provide a key intermediate for preparing anamorelin with a novel structure. The compound is modified with a chiral auxiliary and can prepare the key intermediate compound of formula II in high yield by adopting an asymmetric synthesis strategy without undergoing chiral resolution.

[0011] The first aspect of the present invention provides a compound of formula I-2, or a pharmaceutically acceptable salt thereof,

[0012]

[0013] wherein R1 and R3 are each independently selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S;

[0014] R2 is selected from the following groups: substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C1-C6 alkyl-C6-C10 aryl;

[0015] The substitution refers to substitution by one or more substituents selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, C6-10 aryl, 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S;

[0016] R5 is selected from the group consisting of -Boc, -Cbz, -Tr, -MOM, and -SEM.

[0017] In another preferred embodiment, R2 is selected from the following groups: substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl,

[0018] Y is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and C3-C8 cycloalkyl.

[0019] In another preferred embodiment, R3 is selected from the following groups: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S;

[0020] In another preferred embodiment, the compound of formula I-2 is a compound of formula I-2a,

[0021]

[0022] Wherein, the definitions of R1, R2 and R3 are as described in the first aspect of the present invention.

[0023] In another preferred embodiment, the compound is selected from the following group:

[0024]

[0025]

[0026] The second aspect of the present invention provides a method for preparing the compound according to the first aspect of the present invention, comprising the following steps:

[0027] (a-1) reacting a compound of formula I-1 with a compound of formula B in an inert solvent in the presence of a catalyst to prepare a compound of formula I-2;

[0028]

[0029] Wherein, R1, R2, R3 and R5 are defined as described in the first aspect of the present invention.

[0030] In another preferred embodiment, the catalyst in step (a-1) is selected from the group consisting of TsOH, TfOH, or a combination thereof.

[0031] In another preferred embodiment, the preparation method of the compound of formula B is as follows:

[0032] (aa) preparing a compound of formula B from a compound of formula A in an inert solvent in the presence of a base;

[0033]

[0034] Wherein, R2 and R3 are defined as described in the first aspect of the present invention.

[0035] In another preferred embodiment, the base in step (aa) is selected from the group consisting of triethylamine, diisopropylethylamine, or a combination thereof.

[0036] The third aspect of the present invention provides a use of the compound described in the first aspect of the present invention for preparing an anamorelin intermediate.

[0037] In another preferred embodiment, the anamorelin intermediate has the following structure:

[0038]

[0039] wherein R5 is as defined above.

[0040] In another preferred embodiment, the method for preparing the anamorelin intermediate comprises the following steps:

[0041]

[0042] (a) reacting a compound of formula I-2 with a Bn-X reagent in an inert reagent in the presence of a base to prepare a compound of formula I-3;

[0043] (b) preparing a compound of formula I-4 from a compound of formula I-3 in the presence of an acid and a reducing agent in an inert solvent;

[0044] (c) hydrolyzing a compound of formula I-4 in the presence of a base in an inert solvent to prepare a compound of formula I.

[0045] wherein X is selected from the group consisting of Br, Cl, I,

[0046] R1, R2, R3and R5are as defined in the first aspect of the present application;

[0047] R6is C1-C6alkyl.

[0048] In another preferred embodiment, the step (b) comprises the following steps:

[0049]

[0050] (b-1) reacting a compound of formula I-3 with a reagent of R4-NHNH2in an inert solvent to prepare a compound of formula C;

[0051] (b-2) preparing a compound of formula D from a compound of formula C in the presence of an acid and a reducing agent in an inert solvent;

[0052] (b-3) hydrolyzing a compound of formula D in an inert solvent to prepare a compound of formula I-4;

[0053] wherein R4has the structure

[0054] R7represents 0-3 substituents each independently selected from the group consisting of -NO2, C1-C6alkyl.

[0055] It should be understood that, within the scope of the present application, all the technical features described above and in the following (such as in the examples) of the present application can be combined with each other to form new or preferred technical solutions. Due to the limited space, they are not listed one by one here. BRIEF DESCRIPTION OF DRAWINGS

[0056] Figure 1 The hydrogen spectrum data of compound 1 is shown.

[0057] Figure 2 The hydrogen spectrum data of compound of formula I-3-1 is shown.

[0058] Figure 3 The hydrogen spectrum data of compound of formula I-4-1 is shown.

[0059] Figure 4 The hydrogen spectrum data of compound of formula II is shown. DETAILED DESCRIPTION

[0060] After extensive and in-depth research, the inventors unexpectedly prepared a compound of Formula I-2 modified with a chiral auxiliary. Using the compound of Formula I-2 as a starting material, the compound of Formula I with high chiral purity can be prepared in high yield, without requiring an additional chiral resolution step, and ultimately, anamorelin can be directly prepared. Based on this, the inventors completed the present invention.

[0061] the term

[0062] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0063] In the present invention, the halogen is F, Cl, Br or I.

[0064] In the present invention, the term "C1-C6 alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and n-hexyl. "C1-C10 alkyl" and similar terms have similar definitions.

[0065] In the present invention, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, and the like. "C1-C3 alkoxy" and similar terms have similar definitions.

[0066] In the present invention, the term "C3-C8 cycloalkyl" represents a cyclic aliphatic hydrocarbon group consisting of 3 to 8 ring carbon atoms, and so on; it should be understood that the "cycloalkyl" described in the present invention includes not only monocyclic aliphatic hydrocarbon groups, but also cyclic, spirocyclic and bridged ring systems composed of multiple cyclic aliphatic hydrocarbons; the "cycloalkyl" described in the present invention includes not only aliphatic hydrocarbon groups with fully saturated carbon atoms, but also aliphatic hydrocarbon groups with unsaturated bonds in some of the carbon atoms; examples of the "cycloalkyl" described in the present invention include, but are not limited to: When a cycloalkyl group is used as a substituent, the connection site with the main body of the molecule can occur at any chemical bond-permitted position on the cycloalkyl group. Similar terms such as "C3-C6 cycloalkyl" have similar definitions.

[0067] In the present invention, the term "aryl" refers to a monocyclic ring system and a bicyclic ring system composed of a specific number of carbon atoms and obeying Hückel's rule; it should be understood that when the "aryl" described in the present invention is a bicyclic ring system, it includes not only the case where all rings are aromatic rings, but also the case where only one ring is an aromatic ring and the other ring is a non-aromatic aliphatic ring.

[0068] In the present invention, the term "C6-C10 aryl" refers to a ring system having 6 to 10 carbon atoms, at least one of which is an aromatic ring; examples of the "aryl" of the present invention include but are not limited to etc.; when "aryl" is used as a substituent, the connection site with the main body of the molecule occurs on the aromatic ring.

[0069] In the present invention, the term "heterocycloalkyl" refers to a cyclic group that indicates a specific number of ring atoms, contains at least one ring heteroatom (N, O or S), is saturated or partially unsaturated, and is non-aromatic; it should be understood that the "heterocyclyl" described in the present invention includes not only monocyclic heterocyclic ring systems, but also polycyclic heterocyclic ring systems, such as cyclic, spirocyclic and bridged rings; when the "heterocyclyl" is a polycyclic system, at least one ring contains a ring heteroatom, and the other rings may contain ring heteroatoms or may be cycloalkyl; for example, the term "4-8 membered heterocycloalkyl" refers to a monocyclic or polycyclic ring system with 4 to 8 ring atoms, at least one of which is a heteroatom, saturated or partially unsaturated; the definitions of other similar terms are similar; preferably, the number of heteroatoms is 1 to 3. Including (but not limited to) the following groups: etc.; it should be understood that when a "heterocyclic group" is used as a substituent, the connection site with the main body of the molecule can occur at any chemical bond-allowed position on the "heterocyclic group".

[0070] In the present invention, the term "heteroaryl" refers to a cyclic group with a specific number of ring atoms, containing at least one ring heteroatom (N, O, or S), and having aromatic properties. Unless otherwise specified, the "heteroaryl" herein includes not only monocyclic heteroaromatic systems but also polycyclic heteroaromatic systems, such as bicyclic heteroaromatics, tricyclic heteroaromatics, and tetracyclic heteroaromatics. When the "heteroaryl" is a polycyclic heteroaromatic system, at least one ring is aromatic, and the other rings can be aromatic or non-aromatic, and the heteroatoms can be located in either aromatic or non-aromatic rings. Polycyclic heteroaromatic systems include not only paracyclic systems but also bridged and spirocyclic systems. The term "5-7 membered heteroaryl" refers to a cyclic group with 5 to 7 ring atoms, at least one of which is a heteroatom, and having aromatic properties. The definitions of other similar terms are similar.

[0071] In the present invention, the term "halo" means substituted with halogen.

[0072] In the present invention, the term "optionally" means that when there are a series of candidate groups to choose from, some of them can be selected, or none of them can be selected.

[0073] The term "independently" used in the present invention means that several substituents defined simultaneously do not affect each other when selected from the same series of candidate groups, and they may be the same or different.

[0074] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is the substituent described above or the substituent appearing in the examples. Unless otherwise specified, a substituted group may have a substituent selected from the specific group at any substitutable position of the group, and the substituent may be the same or different at each position. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible.

[0075] In the present invention, the term "1-6" refers to 1, 2, 3, 4, 5 or 6, and other similar terms independently have similar meanings.

[0076] It should be understood that when a group is present at multiple different positions in a compound, its definition at each position is independent of each other and may be the same or different. In other words, the term "selected from the group consisting of:" and the term "each independently selected from the group consisting of:" have the same meaning.

[0077] As used herein, the terms "comprise," "include," and "contain" are used interchangeably to include not only closed definitions but also semi-closed and open definitions. In other words, the terms include "consisting of," "consisting essentially of."

[0078] The "inert solvent" described in the present invention refers to a solvent that does not react with the compounds in the reaction system.

[0079] As used herein, "Toluene" refers to toluene, which has the structure

[0080] As used herein, "Bn-" refers to a benzyl group, the structure of which is

[0081] Refers to the position where a group is attached to other parts of the structure.

[0082] Important intermediate of anamorelin (compound of formula I-2)

[0083] The present invention provides a compound of formula I-2, or a pharmaceutically acceptable salt thereof,

[0084]

[0085] wherein R1, R2, R3 and R5 are as defined above.

[0086] Preferably, R2 is selected from the following groups: substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl,

[0087] Y is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and C3-C8 cycloalkyl.

[0088] Preferably, the compound of formula I-2 is a compound of formula I-2a,

[0089]

[0090] wherein R1, R2, and R3 are as defined above.

[0091] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed between a positively charged group on the compound of formula (I) and an anion, or a salt formed between a negatively charged group on the compound of formula (I) and a cation. Suitable anions include, but are not limited to, chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, toluenesulfonate, tartrate, fumarate, glutamate, glucuronide, lactate, glutarate, or maleate. Suitable cations include, but are not limited to, sodium, potassium, magnesium, calcium, ammonium, and the like.

[0092] In another preferred embodiment, the pharmaceutically acceptable salts of the present invention refer to salts formed by the compound represented by general formula (I) with the following acid groups, such as but not limited to: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, aminosulfonic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, malonic acid, fumaric acid , propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid and isethionic acid, etc.; or a salt formed by the compound represented by general formula (I) and an inorganic base, such as but not limited to sodium salt, potassium salt, calcium salt, aluminum salt or ammonium salt; or a salt formed by the compound represented by general formula (I) and an organic base, such as but not limited to methylamine salt, ethylamine salt, ethanolamine salt, hydroxymethylaminomethane (TRIS) ammonium salt, etc.

[0093] Preparation method of key intermediate of anamorelin

[0094] Typically, the preparation method of the compound of formula I of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.

[0095] The present invention provides a method for preparing a key intermediate of anamorelin, comprising the following steps:

[0096]

[0097] (a) reacting a compound of formula I-2 with a Bn-X reagent in an inert reagent in the presence of a base to prepare a compound of formula I-3;

[0098] (b) preparing a compound of formula I-4 from a compound of formula I-3 in an inert solvent in the presence of an acid and a reducing agent;

[0099] Preferably, X is Br;

[0100] wherein R1, R2, R3 and R5 are as defined above.

[0101] In some embodiments, step (b) comprises the following steps:

[0102]

[0103] (b-1) reacting the compound of formula I-3 with a reagent R4-NHNH2 in an inert solvent to prepare a compound of formula C;

[0104] (b-2) in an inert solvent, in the presence of an acid and a reducing agent, the compound of formula C is reacted to obtain a compound of formula D;

[0105] (b-3) hydrolyzing the compound of formula D in an inert solvent to obtain a compound of formula I-4;

[0106] wherein each group is as defined above.

[0107] In some embodiments, the method further comprises the following steps before step (a):

[0108]

[0109] (a-1) In an inert solvent, in the presence of a catalyst, the compound of formula I-1 reacts with the compound of formula B to prepare the compound of formula I-2.

[0110] wherein R1, R2, R3 and R5 are as defined above.

[0111] In some embodiments, the method is used to prepare an important intermediate of anamorelin (compound of formula I), and the specific steps are as follows:

[0112]

[0113] (c) In an inert solvent, in the presence of a base, the compound of formula I-4 undergoes a hydrolysis reaction to prepare a compound of formula I.

[0114] Wherein, R1 is as defined above.

[0115] The inert solvent is selected from the group consisting of water, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), sulfolane, dichloromethane, dichloroethane, toluene, acetonitrile, alcohol solvents, ether solvents, or combinations thereof.

[0116] Preferably, the inert solvent is selected from the group consisting of dichloromethane, toluene, methanol, ethanol, tetrahydrofuran, or a combination thereof.

[0117] In some embodiments, the reaction time of step (c) is 1 to 12 hours, preferably 2 to 6 hours.

[0118] In some embodiments, the reaction temperature of step (c) is 20-80°C; preferably 40-70°C.

[0119] Specifically, the method comprises the following steps:

[0120]

[0121] In the present invention, the compound of formula B can be purchased through commercial channels or prepared by the method shown in step aa, which is as follows:

[0122] (aa) preparing a compound of formula B from a compound of formula A in an inert solvent in the presence of a base;

[0123]

[0124] Wherein, R2 and R3 are defined as described in the first aspect of the present invention.

[0125] Step a-1, step a, step b-1, step b-2, step b-3 and step c are as defined above.

[0126] The yield of the compound of formula II in the method is 90-95% (calculated based on the compound of formula I-4).

[0127] Compared with the prior art, the main advantages of the present invention are:

[0128] 1. The compound of formula I-2 of the present invention has a novel structure and is modified with a chiral auxiliary agent, and can be directly used to prepare chiral compounds.

[0129] 2. When the present invention uses the compound of formula I-2 as a raw material to prepare the compound, no additional chiral resolution is required, and an important anamorelin intermediate with high chiral purity can be prepared.

[0130] 3. The compounds of the present invention can be used to prepare anamorelin intermediates with high chiral purity in high efficiency and high yield.

[0131] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0132] Unless otherwise stated, the following examples were carried out under normal pressure, and room temperature refers to 20-30°C.

[0133] Example 1 Preparation of Compound 1

[0134]

[0135] B1 (2.57 g, 10 mmol), I-1-1 (1.73 g, 10 mmol), TsOH (100 mg), and Toluene (50 ml) were added to a 250 ml flask and stirred under reflux for 6 h. The reaction solution was concentrated and purified by column chromatography to obtain compound 1 in a yield of 92%. 1 H NMR (400MHz, CDCl3) δ9.22–9.02(m,1H),4.07(s,2H),3.86–3.73(m,1H),3.69(s,3H),3.55–3.42 (m,2H),2.28(q,J=5.6Hz,2H),2.21–2.08(m,1H),1.46(d,J=4.3Hz,18H),1.00(d,J=6.8Hz,6H).

[0136] Example 2 Preparation of Compound 2

[0137]

[0138] Except using I-1-2 and B2 as reaction raw materials, other operations were carried out with reference to Example 1, and the yield was 89%. 1H NMR (400MHz, CDCl3) δ9.24–9.02(m,1H),4.09(s,2H),3.90–3.75(m,1H),3.65(s,3H),3.60–3.50 (m,2H),2.30(q,J=5.6Hz,2H),2.24–2.09(m,1H),1.48(d,J=4.3Hz,18H),1.03(d,J=6.8Hz,9H).

[0139] Example 3 Preparation of Compound 3

[0140]

[0141] Except using I-1-3 and B3 as reaction raw materials, other operations were carried out with reference to Example 1, and the yield was 90%. 1 H NMR (400MHz, CDCl3) δ9.22–9.02(m,1H),7.33-7.50(m,5H),5.02(s,2H),2.28(q,J=5.6Hz,2H),1.46(d,J=4.3Hz,18H),1.00(d,J=6.8Hz,6H).

[0142] Example 4 Preparation of Compound 4

[0143]

[0144] Except using I-1-4 and B4 as reaction raw materials, other operations were carried out with reference to Example 1, and the yield was 90%. 1 H NMR (400MHz, CDCl3) δ8.24–8.02(m,1H),7.33-7.50(m,5H),5.02(s,2H),3.90–3.75(m,1H),3. 65(s,3H),3.60–3.50(m,2H),2.30(q,J=5.6Hz,2H),2.24–2.09(m,2H),1.48(d,J=4.3Hz,18H).

[0145] Example 5 Preparation of Compound 5

[0146]

[0147] Except using I-1-5 and B5 as reaction raw materials, other operations were carried out with reference to Example 1, and the yield was 90%. 1 H NMR (400MHz, CDCl3) δ9.22–9.02(m,1H),7.33-7.50(m,15H),2.28-2.33(m,2H),1.46-1.55(m,18H),1.03-1.12(m,6H).

[0148] Example 6 Preparation of Compound 6

[0149]

[0150] Except using I-1-6 and B6 as the reaction raw materials, other operations were carried out with reference to Example 1, and the yield was 90%. 1 H NMR(400MHz, CDCl3)δ8.25–8.03(m,1H),7.29-7.33(m,15H),5.04(s,2H),3.91–3.74(m,1H), 3.63(s,3H),3.61–3.52(m,2H),2.32(q,J=5.6Hz,2H),2.24–2.08(m,2H),1.49-1.55(m,18H).

[0151] Example 7 Preparation of Compound 7

[0152]

[0153] Except using I-1-7 and B7 as reaction raw materials, other operations were carried out with reference to Example 1, and the yield was 85%. 1 H NMR (400MHz, CDCl3) δ8.74–8.62(m,1H),3.55-3.61(m,5H),3.24-3.33(m,3H),2.07-2.09(m,3H),1.73-1.90(m,8H),1.03(m,18H).

[0154] Example 8 Preparation of Compound 8

[0155]

[0156] Except using I-1-8 and B8 as the reaction raw materials, other operations were carried out with reference to Example 1, and the yield was 82%. 1 H NMR (400MHz, CDCl3) δ8.75–8.63(m,1H),3.57-3.63(m,5H),3.21-3.30(m,4H),1.46-1.63(m,10H),1.03-1.08(m,18H).

[0157] Example 9 Preparation of Compound 9

[0158]

[0159] Except using I-1-9 and B9 as the reaction raw materials, other operations were carried out with reference to Example 1, and the yield was 85%. 1H NMR(400MHz, CDCl3)δ8.74–8.62(m,1H),7.33-7.50(m,5H),5.02(s,2H),3.55-3.61 (m,5H),3.24-3.33(m,3H),2.07-2.09(m,3H),1.73-1.90(m,8H),1.03-1.12(m,9H).

[0160] Example 10 Preparation of Compound 10

[0161]

[0162] Except using I-1-10 and B10 as the reaction raw materials, other operations were carried out in accordance with Example 1, with a yield of 85%. 1 HNMR(400MHz, CDCl3)δ8.75–8.63(m,1H),7.33-7.50(m,5H),5.02(s,2H),3 .57-3.63(m,5H),3.21-3.30(m,4H),1.46-1.63(m,10H),1.03-1.08(m,9H).

[0163] Example 11 Preparation of Compound 11

[0164]

[0165] Except using I-1-11 and B11 as the reaction raw materials, other operations were carried out with reference to Example 1, and the yield was 85%. 1 HNMR(400MHz, CDCl3)δ8.75–8.62(m,1H),7.34-7.50(m,15H),3.58-3.61(m,5H ),3.25-3.33(m,3H),2.00-2.09(m,3H),1.75-1.90(m,8H),1.03-1.15(m,9H).

[0166] Example 12 Preparation of Compound 12

[0167]

[0168] Except using I-1-12 and B12 as the reaction raw materials, other operations were carried out in accordance with Example 1, with a yield of 82%. 1 HNMR (400MHz, CDCl3) δ8.76–8.62(m,1H),7.34-7.50(m,15H),3.57-3.63(m,5H),3.23-3.34(m,4H),1.46-1.63(m,10H),1.03-1.08(m,9H).

[0169] Example 13 Preparation of Compound 13

[0170]

[0171] Except using I-1-13 and B13 as reaction raw materials, other operations were carried out in accordance with Example 1, with a yield of 78%. 1 HNMR (400MHz, CDCl3) δ8.66–8.73(m,1H),3.54-3.64(m,5H),3.18-3.33(m,3H),1.70-2.07(m,17H),1.42-1.46(m,18H).

[0172] Example 14 Preparation of Compound 14

[0173]

[0174] Except using I-1-14 and B14 as reaction raw materials, other operations were carried out with reference to Example 1, and the yield was 65%. 1 HNMR (400MHz, CDCl3) δ8.76–8.83(m,1H),3.64-3.74(m,5H),3.28-3.43(m,3H),1.80-2.07(m,17H),1.44-1.49(m,18H).

[0175] Example 15 Preparation of Compound 15

[0176]

[0177] Except using I-1-15 and B15 as reaction raw materials, other operations were carried out with reference to Example 1, and the yield was 65%. 1 HNMR(400MHz, CDCl3)δ8.76–8.83(m,1H),7.33-7.50(m,5H),5.02(s,2H),3 .64-3.74(m,5H),3.28-3.43(m,3H),1.80-2.07(m,17H),1.44-1.49(m,9H).

[0178] Example 16 Preparation of Compound 16

[0179]

[0180] Except using I-1-16 and B16 as the reaction raw materials, other operations were carried out in accordance with Example 1, with a yield of 65%. 1HNMR (400MHz, CDCl3) δ8.76–8.83(m,1H),7.33-7.50(m,15H),3.64-3.74(m,5H),3.28-3.43(m,3H),1.80-2.07(m,17H),1.44-1.49(m,9H).

[0181] Example 17 Preparation of Compound 17

[0182]

[0183] Except using I-1-17 and B17 as reaction raw materials, other operations were carried out with reference to Example 1, and the yield was 65%. 1 HNMR (400MHz, CDCl3) δ8.76–8.83(m,1H),7.34-7.50(m,15H),3.64-3.74(m,5H),3.28-3.45(m,3H),1.80-2.09(m,17H),1.44-1.52(m,9H).

[0184] Example 18 Preparation of Compound 18

[0185]

[0186] Except using I-1-18 and B18 as the reaction raw materials, other operations were carried out with reference to Example 1, and the yield was 65%. 1 HNMR(400MHz, CDCl3)δ8.76–8.83(m,1H),7.33-7.50(m,5H),5.02(s,2H),3 .64-3.74(m,5H),3.28-3.43(m,3H),1.80-2.07(m,17H),1.44-1.49(m,9H).

[0187] Example 19 Preparation of Anamorelin (Compound of Formula II)

[0188]

[0189] Step aa: A1 (6.3 g, mmol) and 20 ml of dichloromethane were added to a 100 ml flask, and the mixture was stirred in an ice bath for 20 min. Triethylamine (3.87 g, 30 mmol) was then added and stirred for 10 min. The solid disappeared and the solution became turbid. Saturated brine was added to separate the liquid and concentrate to obtain 5.03 g of a colorless liquid (yield 96%).

[0190]

[0191] Step a-1: Same as Example 1.

[0192]

[0193] Step a: Compound 1 (412 mg, 1 mmol) and Toluene (8 ml, dried over anhydrous magnesium sulfate) were added to a 50 ml three-necked flask, replaced with nitrogen, and stirred at -78 ° C for 30 min. LDA (1.2 mmol, 0.6 ml / 2N solution) was added and continued to stir for 1 h. HMPT (179 mg, 1 mmol) was added and continued to stir for 1 h. After adding Bn-Br (342 mg, 2 mmol), it was stirred at -78 ° C for 12 h. A small amount of product was generated. It was subsequently transferred to -40 ° C and stirred for 24 h. The reaction was monitored and the product increased significantly. Methanol and brine were added to quench the reaction, extracted with EA, dried over anhydrous sodium sulfate, concentrated, and column chromatography to obtain 323 mg of compound I-3-1 with a yield of 85% and an ee value of 99.2%. 1H NMR (400MHz, CDCl3) δ7.30–7.10(m,5H),4.58(d,J=13.6Hz,1H),4.11(q,J=7.2Hz,1H),3.61(s,3H),3.25(d,J=13.9Hz ,1H),3.21–3.10(m,1H),3.04(d,J=13.6Hz,2H),2.68(ddd,J=14.6,10.5,6.6Hz,1H),2.49–2.32(m,1H),1.45(s,9H).

[0194]

[0195] Step b-1: Add I-3-1 (3 mmol, 1041 mg), TsNHNH2 (3 mmol, 558 mg), and MeOH (15 ml) to a 100 ml flask and stir at 70°C for 4 h. The reaction is complete with complete conversion of the starting materials. Concentrate to afford a white foamy solid in 100% yield. EE value: 99.1%.

[0196]

[0197] Step b-2: THF (25 ml) and MeOH (25 ml) were added to the concentrated solid, and the mixture was stirred at 25°C until the solid completely dissolved. CF3COOH was added, the pH was adjusted to 3, and the mixture was stirred for 1 hour. NaBH3CN (2 mmol, 126 mg) was added and stirring continued for 3 hours. HPLC monitoring indicated complete disappearance of starting material C1, indicating conversion to intermediate D1. EE value: 99.0%.

[0198]

[0199] Step b-3: The reaction system was concentrated, ethanol (73 ml) and anhydrous sodium acetate (9.8 g, 120 mmol) were added, and stirred at 70°C for 1.5 h. The starting material disappeared after TLC monitoring. The mixture was filtered, concentrated, and subjected to column chromatography to obtain 11.06 g of compound I-4-1, with a yield of 98%. 1 The structure was confirmed to be correct by HNMR and the ee value was 99.4% by chiral HPLC. 1 HNMR (600MHz, CDCl3) δ7.26–7.23(m,2H),7.21(t,J=7.2Hz,1H),7.07(dd,J=6.9,1.8Hz,2H),3.99(s,1H),3.60( s,4H),3.13(s,2H),2.93(d,J=13.4Hz,1H),2.75(d,J=13.4Hz,1H),2.02(s,1H),1.69–1.50(m,3H),1.45(s,9H).

[0200]

[0201] Step c: To a 50 ml flask, I-4-1 (1 mmol, 330 mg), NaOH (4 mmol, 160 mg), THF (2 ml), MeOH (4 ml), and H2O (4 ml) were added. The mixture was stirred at 70°C for 6 h. The starting material disappeared after TLC monitoring. The reaction system was concentrated until residual water remained. 15 ml of water and 20 ml of ethyl acetate were added to the system for extraction. The aqueous phase was collected and saturated aqueous tartaric acid was added under ice-cooling conditions to adjust the pH to 3-4. 30 ml of ethyl acetate was added to the system for extraction. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 287 mg of compound II in a 90% yield. EE value: 99.5%. 1 H NMR (400MHz, CDCl3) δ7.27(d,J=6.1Hz,1H),7.26–7.20(m,2H),7.17–7.11(m,2H),5.30(s,1H),4.01(d,J=13.4Hz,1H),3.63(dt,J=13.3,4 .6Hz,1H),3.12(d,J=13.0Hz,2H),2.95(d,J=13.5Hz,1H),2.81(d,J=13.4Hz,1H),2.03(d,J=10.0Hz,1H),1.73–1.55(m,2H),1.44(s,9H).

[0202] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound of formula I-2, or a stereoisomer, enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt thereof, in, R1 and R3 are each independently selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S; R2 is selected from the following groups: substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C1-C6 alkyl-C6-C10 aryl; The substitution refers to substitution by one or more substituents selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, C6-10 aryl, 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S; R5 is selected from the group consisting of -Boc, -Cbz, -Tr, -MOM, and -SEM.

2. The compound according to claim 1, wherein R2 is selected from the following groups: substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, Wherein, Y is selected from the following group: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl.

3. The compound according to claim 1, wherein R3 is selected from the following groups: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S.

4. The compound according to claim 1, wherein The compound of formula I-2 is a compound of formula I-2a, Wherein, R1, R2, and R3 are defined as described in claim 1.

5. The compound according to claim 1, wherein The compound is selected from the group consisting of:

6. A method for preparing the compound according to claim 1, characterized in that: The following steps are involved: (a-1) reacting a compound of formula I-1 with a compound of formula B in an inert solvent in the presence of a catalyst to prepare a compound of formula I-2; Wherein, R1, R2, R3 and R5 are defined as in claim 1.

7. The method according to claim 6, wherein The catalyst in step (a-1) is selected from the group consisting of TsOH, TfOH, or a combination thereof.

8. The method according to claim 6, wherein The preparation method of the compound of formula B is as follows: (aa) preparing a compound of formula B from a compound of formula A in an inert solvent in the presence of a base; Wherein, R2 and R3 are as defined in claim 1.

9. A use of the compound according to claim 1, characterized in that, Used to prepare anamorelin intermediates.

10. The use according to claim 9, characterized in that The following steps are involved: (a) reacting a compound of formula I-2 with a Bn-X reagent in an inert reagent in the presence of a base to prepare a compound of formula I-3; (b) preparing a compound of formula I-4 from a compound of formula I-3 in an inert solvent in the presence of an acid and a reducing agent; (c) hydrolyzing the compound of formula I-4 in an inert solvent in the presence of a base to prepare a compound of formula I; Wherein, X is selected from the following group: Br, Cl, I, R1, R2, R3 and R5 are as defined in claim 1; R6 is a C1-C6 alkyl group.

Images